Targeting inflammatory signaling in obsessive compulsive disorder: a promising approach.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder. Approximately, around 2% to 3% percent of the general population experience symptoms of OCD over the course of their lifetime. OCD can lead to economic burden, poor quality of life, and disability. The characteristic features exhibited generally in OCD are continuous intrusive thoughts and periodic ritualized behaviours. Variations in genes, pathological function of Cortico-Striato-Thalamo-Cortical (CSTC) circuits and dysregulation in the synaptic conduction have been the major factors involved in the pathological progression of OCD. However, the basic mechanisms still largely unknown. Current therapies for OCD largely target monoaminergic neurotransmitters (NTs) in specific dopaminergic and serotonergic circuits. However, such therapies have limited efficacy and tolerability. Drug resistance has been one of the important reasons reported to critically influence the effectiveness of the available drugs. Inflammation has been a crucial factor which is believed to have a significant importance in OCD progression. A significant number of proinflammatory cytokines have been reportedly amplified in patients with OCD. Mechanisms of drug treatment involve attenuation of the symptoms via modulation of inflammatory signalling pathways, modification in brain structure, and synaptic plasticity. Hence, targeting inflammatory signaling may be considered as a suitable approach in the treatment of OCD. The present review focuses mainly on the significant findings from the animal and human studies conducted in this area, that targets inflammatory signaling in neurological conditions. In addition, it also focusses on the therapeutic approaches that target OCD via modification of the inflammatory signaling pathways.

Nanoconstructs for theranostic application in cancer: Challenges and strategies to enhance the delivery.

Nanoconstructs are made up of nanoparticles and ligands, which can deliver the loaded cargo at the desired site of action. Various nanoparticulate platforms have been utilized for the preparation of nanoconstructs, which may serve both diagnostic as well as therapeutic purposes. Nanoconstructs are mostly used to overcome the limitations of cancer therapies, such as toxicity, nonspecific distribution of the drug, and uncontrolled release rate. The strategies employed during the design of nanoconstructs help improve the efficiency and specificity of loaded theranostic agents and make them a successful approach for cancer therapy. Nanoconstructs are designed with a sole purpose of targeting the requisite site, overcoming the barriers which hinders its right placement for desired benefit. Therefore, instead of classifying modes for delivery of nanoconstructs as actively or passively targeted systems, they are suitably classified as autonomous and nonautonomous types. At large, nanoconstructs offer numerous benefits, however they suffer from multiple challenges, too. Hence, to overcome such challenges computational modelling methods and artificial intelligence/machine learning processes are being explored. The current review provides an overview on attributes and applications offered by nanoconstructs as theranostic agent in cancer.

Formulation and optimization of efavirenz nanosuspensions using the precipitation-ultrasonication technique for solubility enhancement.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor, and is classified as BCS Class II API. Its erratic oral absorption and poor bioavailability make it a potential candidate for being formulated as a nanosuspension. The objective of this study was to formulate efavirenz nanosuspensions employing the antisolvent precipitation-ultrasonication method, and to enhance its solubility by reducing particle size to the nanometer range. The effects of different process parameters were studied and optimized with respect to particle size and poly dispersity index (PDI). The optimized formulation was also subjected to lyophilization, to further increase the solubility and stability, and the technology is potentially suited to a range of poorly water-soluble compounds.

Eudragit S100 Coated Citrus Pectin Nanoparticles for Colon Targeting of 5-Fluorouracil.

In the present study, Eudragit S100 coated Citrus Pectin Nanoparticles (E-CPNs) were prepared for the colon targeting of 5-Fluorouracil (5-FU). Citrus pectin also acts as a ligand for galectin-3 receptors that are over expressed on colorectal cancer cells. Nanoparticles (CPNs and E-CPNs) were characterized for various physical parameters such as particle size, size distribution, and shape etc. In vitro drug release studies revealed selective drug release in the colonic region in the case of E-CPNs of more than 70% after 24 h. In vitro cytoxicity assay (Sulphorhodamine B assay) was performed against HT-29 cancer cells and exhibited 1.5 fold greater cytotoxicity potential of nanoparticles compared to 5-FU solution. In vivo data clearly depicted that Eudragit S100 successfully guarded nanoparticles to reach the colonic region wherein nanoparticles were taken up and showed drug release for an extended period of time. Therefore, a multifaceted strategy is introduced here in terms of receptor mediated uptake and pH-dependent release using E-CPNs for effective chemotherapy of colorectal cancer with uncompromised safety and efficacy.

Assessment of lactoferrin-conjugated solid lipid nanoparticles for efficient targeting to the lung.

The aim of the present study was to develop a target oriented drug delivery system for the lungs. Lactoferrin (Lf)-coupled solid lipid nanoparticles (SLNs) bearing rifampicin was prepared by a solvent injection method. The prepared nanoparticles were characterized for shape, particle size, polydispersity and percentage drug entrapment. An optimized formulation was then studied for its in vivo performance in animals and to determine its targeting efficiency. It was observed that, upon coupling with Lf, the size of SLNs increased while the percent entrapment efficiency decreases. In in vitro release, determined by a dialysis technique, analysis showed that uncoupled SLNs exhibited higher drug release as compared to coupled SLNs. An in vivo biodistribution study shows 47.7 ±0.4 drug uptakes by the lungs, which was 3.05 times higher in comparison to uncoupled SLNs. These biodistribution studies are further supported by the fluorescence study that revealed enhanced uptake of Lf-coupled SLNs in the lung. From the presented results, it can be concluded that Lf-coupled SLNs enhanced drug uptake in the lung. Moreover, lactoferrin is an efficient molecule that can be used for targeting active agents directly to the lung.

Targeting liver cancer via ASGP receptor using 5-FU-loaded surface-modified PLGA nanoparticles.

CONTEXT: Liver cancer is widespread liver malignancy in the world, for an estimated one million deaths annually. OBJECTIVE: In present work, lactobionic acid conjugated PLGA nanoparticles (LDNPs) bearing 5-Fluorouracil (5-FU) were developed for targeted delivery to hepatocellular carcinoma. MATERIALS AND METHODS: Lactobionic acid conjugated PLGA was used to prepare LDNPs using modified emulsion diffusion method. RESULTS: They were characterised for particle morphology, particle size (below 150 nm), zeta potential and polydispersity index (PDI ∼0.35), entrapment efficiency (∼60.23%), and cumulative percent drug release. DISCUSSION: LDNPs in ex-vivo cell line studies on human cancer cell line HepG2 exhibited significantly higher cytotoxicity compared to 5-FU and DNPs (unconjugated PLGA NPs) with growth inhibition 50% (GI50) of 66.7 µg/mL, 50.2 µg/mL and 35.5 µg/mL, respectively. In vivo studies exhibited higher drug concentration about 37.52 ± 0.68% in liver as compared to other organs and plasma. CONCLUSION: Thus, LDNPs showed high drug loading, specificity, biocompatibility and efficacy in treatment of liver cancer.

Development and validation of the HPLC method for simultaneous estimation of Paclitaxel and topotecan.

A simple, rapid, accurate and precise high performance liquid chromatography (HPLC) method for simultaneous analysis of Paclitaxel and Topotecan was developed. Different analytical parameters, such as linearity, accuracy, precision, specificity with intentional degradation, limit of detection and limit of quantification (LOQ), were determined according to the ICH guidelines. Acetonitrile-water (70:30, 0.1% trifluoroacetic acid) was run on a Phenomenex Luna C-18(2) column in isocratic mode at a flow rate of 1.2 mL/min for simultaneous analysis of the two drugs using a UV detector set at 227 nm. The proposed method showed a retention time (Rt) of 14.56 min for Topotecan and 23.81 min for Paclitaxel with a continuous run up to 30 min. The linearity of the calibration curves for each analyte in the desired concentration range was found to be good (r(2) > 0.9995). The recovery ranged from 97.9 to 101% for each drug with a relative standard deviation (%RSD) of <2%. Peaks corresponding to each of the drugs exhibited  positive values for the minimum peak purity index over the entire range of integrated chromatographic peak indicating high purity of the peaks. Stability analysis revealed that the drugs remained stable for sufficient time. Thus, the developed method was found to be robust and it can be employed to quantify Paclitaxel and Topotecan in commercial sample and rat blood/serum.

Peptide and protein delivery using new drug delivery systems.

Pharmaceutical and biotechnological research sorts protein drug delivery systems by importance based on their various therapeutic applications. The effective and potent action of the proteins/peptides makes them the drugs of choice for the treatment of numerous diseases. Major research issues in protein delivery include the stabilization of proteins in delivery devices and the design of appropriate target-specific protein carriers. Many efforts have been made for effective delivery of proteins/peptidal drugs through various routes of administrations for successful therapeutic effects. Nanoparticles made of biodegradable polymers such as poly lactic acid, polycaprolactone, poly(lactic-co-glycolic acid), the poly(fumaric-co-sebacic) anhydride chitosan, and modified chitosan, as well as solid lipids, have shown great potential in the delivery of proteins/peptidal drugs. Moreover, scientists also have used liposomes, PEGylated liposomes, niosomes, and aquasomes, among others, for peptidal drug delivery. They also have developed hydrogels and transdermal drug delivery systems for peptidal drug delivery. A receptor-mediated delivery system is another attractive strategy to overcome the limitation in drug absorption that enables the transcytosis of the protein across the epithelial barrier. Modification such as PEGnology is applied to various proteins and peptides of the desired protein and peptides also increases the circulating life, solubility and stability, pharmacokinetic properties, and antigenicity of protein. This review focuses on various approaches for effective protein/peptidal drug delivery, with special emphasis on insulin delivery.

Insulin delivery through nasal route using thiolated microspheres.

The aim of the present study was to investigate the potential of developed thiolated microspheres for insulin delivery through nasal route. In the present study, cysteine was immobilized on carbopol using EDAC. A total of 269.93 µmol free thiol groups per gram polymer were determined. The prepared nonthiolated and thiolated microspheres were studied for particle shape, size, drug content, swellability, mucoadhesion and in vitro insulin release. The thiolated microspheres exhibited higher mucoadhesion due to formation of covalent bonds via disulfide bridges with the mucus gel layer. Drug permeation through goat nasal mucosa of nonthiolated and thiolated microspheres were found as 52.62 ± 2.4% and 78.85 ± 3.1% in 6 h, respectively. Thiolated microspheres bearing insulin showed better reduction in blood glucose level (BGL) in comparison to nonthiolated microspheres as 31.23 ± 2.12% and 75.25 ± 0.93% blood glucose of initial BGL were observed at 6 h after nasal delivery of thiolated and nonthiolated microspheres in streptozotocin-induced diabetic rabbits.

A new horizon in modifications of chitosan: syntheses and applications.

Chitosan is a naturally occurring biopolymer having diversified applications not only in the pharmaceutical field, but also in the biomedical profession. The presence of functional groups, i.e., hydroxyl, acetamido, and amine in the chitosan parent backbone, makes it a suitable candidate for chemical modification, and introduces desired physicochemical and biochemical properties, without any changes in its fundamental skeleton. The various modifications, i.e., alkylation, acylation, quaternization, hydroxyalkylation, carboxyalkylation, thiolation, sulfation, phosphorylation, enzymatic modifications, oligomerization, and graft copolymerization with assorted modifications, and their pharmaceutical and biomedical applications, are discussed in this article. Additionally, it is also limelighted how the chemically engineered chitosan has established a better place with regard to the vista of applications in the arena of sciences such as pharmaceutical, biomedical, biotechnological, tissue engineering, the textile industry, chemistry, the food industry, and many more. This review, hopefully, could enrich knowledge and bring forth new thoughts in line with progress in chitosan polymer science.

Development of surface-functionalised nanoparticles for FGF2 receptor-based solid tumour targeting.

The surface-functionalised gelatin nanoparticles (GNPs) containing cisplatin were developed and characterised for breast cancer targeting using fibroblast growth factor-2 (FGF2) receptors which are overexpressed on breast cancer cells. The GNPs were prepared using two-step desolvation method and then the surface of GNPs was functionalised with activated heparin. They were characterised for surface morphology, particle size and size distribution, surface charge, entrapment efficiency and in vitro drug release. The results revealed that the mean diameter of GNPs was 173 ± 2.2 nm with smooth surface, which was increased to 189 ± 3.4 nm after coupling with heparin (H-GNPs). The targeting effect of H-GNPs and GNPs was investigated by in vitro cell uptake study on human breast cancer MDA-MB-231 cell line, which exhibited greater uptake of H-GNPs as compared to GNPs. Therefore, it is suggested that H-GNPs can be used as an effective carrier for solid tumour targeting.

Mannosylated liposomes bearing Amphotericin B for effective management of visceral Leishmaniasis.

The cationic and mannosylated liposomes were prepared using the cast film method and compared for their antileishmaniasis activity. The surface of the Amphotericin B (Amp B)-bearing cationic multilamellar liposomes was covalently coupled with p-aminophenyl-α-D-mannoside using glutaraldehyde as a coupling agent, which was confirmed by agglutination of the vesicles with concanavalin A. The prepared liposomes were characterized for shape, size, percent drug entrapment, vesicle count, zeta potential, and in vitro drug release. Vesicle sizes of cationic and mannosylated liposomes were found to be 2.32 ± 0.23 and 2.69 ± 0.13 µm, respectively. Zeta potential of cationic liposomes was higher (30.38 ± 0.3 mV), as compared to mannosylated liposomes (17.7 ± 0.8 mV). Percentage drug release from cationic and mannose-coupled liposomes was found to be 45.7% ± 3.1 and 41.9% ± 2.8, respectively, after 24 hours. The in vivo antileishmanial activity was performed on Leishmania donovani-infected golden hamster, and results revealed that Amp B solution was reduced by 42.5 ± 1.8% in the parasite load, whereas the placebo cationic liposomes and drug-containing cationic liposomes showed a reduced parasite load (i.e., 28.1 ± 1.5 and 61.2 ± 3.2%, respectively). The mannose-coupled liposomes showed a maximum reduction in parasite load (i.e., 78.8 ± 3.9%). The biodistribution study clearly showed the higher uptake of mannosylated liposomes in the liver and spleen and hence the active targeting to the reticular endothelial system, which, in turn, would provide a direct attack of the drug to the site where the pathogen resides, rendering the other organs free and safe from the toxic manifestations of the drug.

Steroid-coupled liposomes for targeted delivery to tumor.

The steroidal receptors play a key role in protein synthesis and maintain the homeostasis in normal and diseased state, including tumorigenesis at the target tissues when overactivated. Thus steroidal receptors may act as potential targets for selective delivery of different therapeutic agents as they are overexpressed by a number of endocrinal tumors. The selective delivery of these agents may be a better treatment strategy for endocrinal cancer as it may also result in cytosolic and nuclear delivery of cytotoxic agents. In this review, the targeting potential of steroidal receptors for the drug or bioactive(s) delivery is discussed. The ligands that have been proven to be effective for specific steroidal receptors can be used as vectors for carrying the drug or drug-delivery system to the desired site of drug action in an optimum concentration. This strategy will not only minimize the undesired side effects associated with nonspecific delivery of drug, but will also maximize the drug utilization. Ligand-conjugated liposomes as a carrier of bioactives prevent passive diffusion of the encapsulated drug to normal cells, increase the time of circulation and reduce the undesirable side effects of a drug.

Colloidosomes: an emerging vesicular system in drug delivery.

The application of colloidal and nanoparticulate carrier systems in the biomedical field has changed the definitions of diagnosis, treatment, and disease management. Carrier systems such as liposomes, polymeric particles, and micro-emulsion droplets are used for the sustained release of drugs, pesticides, fragrances, and other substances. Although such delivery systems are widely employed in specialized areas such as gene delivery, targeting to brain, tumor targeting, and oral vaccine formulations, problems associated with their stability and permeability are often encountered, thereby limiting their general application. In the series of vesicular systems, colloidosomes are emerging as a potential tool for controlled delivery of drugs as well as of cosmetics and food supplements. Colloidosomes are solid microcapsules formed by the self-assembly of colloidal particles at the interface of emulsion droplets. Colloidosomes offer precise control over their size, permeability, compatibility, and mechanical strength and can be prepared with an aqueous, aqueous gel, or oily core. This review focuses on the types, fabrication techniques, and stability of colloidosomes.